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Purpose: The aim of this study was to investigate the therapeutic efficacy of the alpha-radioimmunotherapy of ovarian cancer in mice, using different specific activities. This study was performed by using the monoclonal antibody, MX35 F(ab')(2), labeled with the alpha-particle-emitter, 211At., Methods: Animals were intraperitoneally inoculated with approximately 1 x 10(7) cells of the cell line, NIH:OVCAR-3. Four (4) weeks later, five groups of animals were given 400 kBq of 211At-MX35 F(ab')(2) with specific activities equal to 130, 65, 32, 16, or 4 kBq/microg, respectively (n = 18 in each group). As controls, animals were given unlabeled MX35 F(ab')(2) (n = 12). Eight (8) weeks after treatment, the animals were sacrificed and the presence of macro- and microscopic tumors and ascites was determined., Results: The tumor-free fractions (TFFs) of the animals, defined as the fraction of animals with no macro- and microtumors and no ascites, were 0.67, 0.73, 0.50, 0.50, and 0.17 when treated as above. Only the TFF of 0.17, for the specific activity of 4 kBq/microg, was significantly less, compared to that of the specific activity of 130 kBq/microg. The TFF for the specific activity of 4 kBq/microg showed a significant lowering, compared to the specific activity of 130 kBq/microg (p < 0.05). Treatment with unlabeled MX35 F(ab')(2) resulted in a TFF of zero., Conclusions: A specific activity-dependent therapeutic outcome could not be shown in the interval of 130- to 16 kBq/mug. For lower specific activities (i.e., 4 kBq/microg), the therapeutic efficacy was significantly lowered.

Objectives: Analyze morbidity and survival after pelvic exenteration (PE) of gynecological malignancies., Methods: We reviewed 106 consecutive patients with gynecologic malignancies who underwent PE from June 1996 to April 2007 at the Division of Gynecology, European Institute of Oncology (IEO), Milan., Results: PE was performed for cancer of the cervix (62 patients), vagina (21 patients), vulva (9 patients), endometrium (9 patients), ovary (4 patients) and 1 uterine sarcoma. Mean age was 53.6 (30-78) years. 97% of the patients received radiotherapy before PE and 3 patients had PE as primary treatment. We performed 53 anterior, 48 total and 5 posterior PE. Median operation time, estimated blood loss and hospital stay were respectively 490 (200-780) minutes, 1240 (300-6500) ml and 21.6 (11-55) days. No residual tumor was left in 93% of the patients. Median follow-up was 22.3 (1.6-117) months. There were no post-operative deaths (<30 days from surgery) nor intra-operative mortality. Total morbidity rate was 66%; 48% of patients had early complications (<30 days after PE) whereas 52 patients (48.5%) had late complications; 70% of these occurred to the urinary tract and 25% were due to bowel occlusions or fistulas. Overall survival was 52%, 35%, 19% and 16% respectively for cervical, endometrial, vaginal and vulvar cancer., Conclusions: PE is a feasible technique with no post-operative mortality and high percentage of long-survivors, although the morbidity rate still remains significantly high. Careful patient selection, pre- and post-operative care and optimal surgical skills in a Gynecologic Oncologic Center are the cornerstones to further improve quality of life and survival for these patients.

Unlabelled: The alpha-emitter (211)At labeled to a monoclonal antibody has proven safe and effective in treating microscopic ovarian cancer in the abdominal cavity of mice. Women in complete clinical remission after second-line chemotherapy for recurrent ovarian carcinoma were enrolled in a phase I study. The aim was to determine the pharmacokinetics for assessing absorbed dose to normal tissues and investigating toxicity., Methods: Nine patients underwent laparoscopy 2-5 d before the therapy; a peritoneal catheter was inserted, and the abdominal cavity was inspected to exclude the presence of macroscopic tumor growth or major adhesions. (211)At was labeled to MX35 F(ab')(2) using the reagent N-succinimidyl-3-(trimethylstannyl)-benzoate. Patients were infused with (211)At-MX35 F(ab')(2) (22.4-101 MBq/L) in dialysis solution via the peritoneal catheter. gamma-Camera scans were acquired on 3-5 occasions after infusion, and a SPECT scan was acquired at 6 h. Samples of blood, urine, and peritoneal fluid were collected at 1-48 h. Hematology and renal and thyroid function were followed for a median of 23 mo., Results: Pharmacokinetics and dosimetric results were related to the initial activity concentration (IC) of the infused solution. The decay-corrected activity concentration decreased with time in the peritoneal fluid to 50% IC at 24 h, increased in serum to 6% IC at 45 h, and increased in the thyroid to 127% +/- 63% IC at 20 h without blocking and less than 20% IC with blocking. No other organ uptakes could be detected. The cumulative urinary excretion was 40 kBq/(MBq/L) at 24 h. The estimated absorbed dose to the peritoneum was 15.6 +/- 1.0 mGy/(MBq/L), to red bone marrow it was 0.14 +/- 0.04 mGy/(MBq/L), to the urinary bladder wall it was 0.77 +/- 0.19 mGy/(MBq/L), to the unblocked thyroid it was 24.7 +/- 11.1 mGy/(MBq/L), and to the blocked thyroid it was 1.4 +/- 1.6 mGy/(MBq/L) (mean +/- SD). No adverse effects were observed either subjectively or in laboratory parameters., Conclusion: This study indicates that by intraperitoneal administration of (211)At-MX35 F(ab')(2) it is possible to achieve therapeutic absorbed doses in microscopic tumor clusters without significant toxicity.

A 34-year-old woman was referred to our hospital with ileus. She had undergone surgical resection following chemotherapy for yolk sac tumor at the age of 12 years, and had received additional surgery and radiation therapy for a local recurrence at age 13. Following evaluation, a sigmoid colon tumor was detected and was surgically resected. Histology proved well differentiated adenocarcinoma with chronic irradiation colitis, suggesting that irradiation may have induced the colon cancer.

Objective: To highlight aspects of malignant ovarian sex cord stromal tumors, effects of treatment, and developments over the past 28 years., Design: Population-based cohort study., Setting: Gynecological departments within the catchment-area of the Munich Cancer Registry and associated with the project group 'Malignant Ovarian Tumors' of the Munich Cancer Center., Sample: One hundred and forty-five women with an invasive single sex cord stromal tumor diagnosed between 1978 and 2005., Methods: Overall survival was estimated with the Kaplan-Meier method, relative survival was computed by the ratio of observed to expected survival rate. The impact of age, International Federation of Gynecology and Obstetrics (FIGO)-stage, residual tumor, and chemotherapy was examined by multivariate analysis (Cox regression model)., Main Outcome Measures: Overall and relative survival and multivariate adjusted overall survival., Results: Survival data showed a five-/10-year overall survival of 55.8%/42.8% (relative survival 58.6%/49.2%) for women diagnosed before 1988 and 89.1%/78.3% (relative survival 92.7%/85.2%) for women diagnosed after 1988. After adjustment for age and FIGO-stage, the following hazard ratios and 95% confidence intervals (95% CI) for treatment methods resulted: 3.3 (95% CI 1.5-7.0) for women with compared to women without residual tumor and 2.2 (95% CI 1.2-4.2) for women with chemotherapy compared to women where no chemotherapy was given., Conclusions: Improvements in survival may be attributed to a stage-shift toward more favorable stages at diagnosis and to advances in treatment such as improved surgery without residual tumor. There is no evidence for any benefit of adjuvant chemotherapy. Surgery remains the cornerstone of treatment, yet the benefit of postoperative therapy is still under debate.

Ovarian choriocarinoma is a rare tumor and has not been described before in a true hermaphrodite condition. A 23-year-old karyotype 46XX parous female was admitted to hospital because of amenorrhea, irregular vaginal bleeding, an adnexal mass, and an increased beta-hCG serum level. Ectopic pregnancy was suspected three times and exploratory laparoscopy done each time removing the right ovarian mass and local pelvic and omental spread. Final pathology revealed a true hermaphrodite state with testicular tissue with distinct tubules, ovarian tissue with follicles, and ovarian choriocarinoma with necrosis and hemorrhage. She received chemotherapy followed by radical pelvic surgery.

Numerous pathologies and their treatments may alter ovarian reserve in women and girls and may harm their future fertility. Oocytes cryopreservation techniques may be used in a limited number of cases, excluding young patients. We hereby report results obtained with our and other teams' ovarian tissue vitrification techniques. This new approach can be offered to young patients before puberty and should not delay both chemotherapy and radiotherapy when needed. Major drawbacks include potential alteration of ovarian reserve, as well as recurrence of the original malignancy. The later can be circumvented using in vitro maturation techniques. It is important to discuss fertility preservation opportunities with every woman or girls facing potential premature ovarian failure.

We investigated whether epithelial ovarian cancer patients participating in a randomized phase III trial comparing single intraperitoneal (IP) administration of yttrium-90-labeled murine HMFG1 ((90)Y-muHMFG1) plus standard treatment (AT) vs. standard treatment (ST) alone developed IgG ab to MUC1 that had an impact on disease outcome. Serial serum samples from 208 patients in the AT and 199 patients in the ST arm were tested for IgG ab to MUC1 (anti-MUC1 IgG). Anti-MUC1 IgG at weeks 4, 8 and 12 ranked higher in the AT than in the ST arm (p < 0.001). The median (range) area under the curve (AUC) of anti-MUC1 IgG for weeks 1 to 12 was 5.53 (1.51-39.51) and 3.92 (1.17-68.74) for the AT and ST arm, respectively (p < 0.001). An anti-MUC1 IgG AUC > 13 was associated with a benefit in overall survival (OS) and disease-free survival (DFS) in the AT arm in univariate (p = 0.043 and 0.036, respectively), but not in multivariate analysis (Cox proportional hazards regression model). Kaplan-Meier analysis showed a benefit in OS and DFS in patients with an anti-MUC1 IgG AUC > 13 in the AT arm (p = 0.043 and 0.036, respectively), but not in the ST arm. A single IP injection with muHMFG1 did not lead to a survival benefit in the randomized trial, but it induced ab to MUC1 that were associated with an improved disease outcome in patients with highest levels of anti-MUC1 IgG. Immunotherapy against MUC1 could be effective in the treatment of epithelial ovarian cancer.

Purpose: Pain is a common symptom among cancer patients, yet many patients do not receive adequate pain management. Few data exist quantifying analgesic use by radiation oncology patients. This study evaluated the causes of pain in cancer patients and investigated the reasons patients fail to receive optimal analgesic therapy., Methods and Materials: An institutional review board-approved, Internet-based questionnaire assessing analgesic use and pain control was posted on the OncoLink (available at www.oncolink.org) Website. Between November 2005 and April 2006, 243 patients responded. They were predominantly women (73%), white (71%), and educated beyond high school (67%) and had breast (38%), lung (6%), or ovarian (6%) cancer. This analysis evaluated the 106 patients (44%) who underwent radiotherapy., Results: Of the 106 patients, 58% reported pain from their cancer treatment, and 46% reported pain directly from their cancer. The pain was chronic in 51% and intermittent in 33%. Most (80%) did not use medication to manage their pain. Analgesic use was significantly less in patients with greater education levels (11% vs. 36%, p = 0.002), with a trend toward lower use by whites (16% vs. 32%, p = 0.082) and women (17% vs. 29%, p = 0.178). The reasons for not taking analgesics included healthcare provider not recommending medication (87%), fear of addiction or dependence (79%), and inability to pay (79%). Participants experiencing pain, but not taking analgesics, pursued alternative therapies for relief., Conclusions: Many radiation oncology patients experience pain from their disease and cancer treatment. Most study participants did not use analgesics because of concerns of addiction, cost, or failure of the radiation oncologist to recommend medication. Healthcare providers should have open discussions with their patients regarding pain symptoms and treatment.

Background: Human anti-mouse antibody (HAMA)-IgM and IgG in ovarian cancer patients treated with intraperitoneal (i.p.) 90Y-muHMFG1 as consolidating therapy were analyzed for a relationship with outcome of disease., Patients and Methods: Serial serum samples from 208 ovarian cancer patients participating in a phase III trial of i.p. 90Y-muHMFG1 and 25 controls were analyzed for HAMA-IgM and HAMA-IgG. Results were correlated with time to, and location of, disease recurrence., Results: Patients receiving i.p. 90Y-muHMFG1 developed a rapid HAMA-IgM peak (week 4 to 8), followed by a HAMA-IgG peak 2-4 weeks later. HAMA levels in the control group remained unchanged. Early maximum HAMA-IgG peaks were associated with early relapse [hazard ratio (HR), 0.975; 95% confidence interval (CI) 0.956 to 0.995; p=0.012]. Patients with a HAMA-IgG maximum before or at 8 weeks were at significantly higher risk for disease recurrence (HR, 1.6; 95% CI 1.1 to 25;p=0.021) as compared to patients with a HAMA-IgG maximum after 8 weeks., Conclusion: Besides time point of maximum HAMA-IgG, no evident relation could be found between HAMA-IgM or HAMA-IgG development and time to relapse or location of recurrence.

The alpha(v)beta(3) integrin plays a pivotal role in angiogenesis and tumor metastasis. Angiogenic blood vessels overexpress alpha(v)beta(3) integrin, as in tumor neovascularization, and alpha(v)beta(3) integrin expression in other microvascular beds and organs is limited. Therefore, alpha(v)beta(3) integrin is a suitable receptor for tumor-targeting imaging and therapy. Recently, tetrameric and dimeric RGD peptides have been developed to enhance specificity to alpha(v)beta(3) integrin. In comparison to the corresponding monomeric peptide, however, these peptides show high levels of accumulation in kidney and liver. The purpose of this study is to evaluate tumor-targeting properties and the therapeutic potential of 111In- and 90Y-labeled monomeric RGD peptides in BALB/c nude mice with SKOV-3 human ovarian carcinoma tumors. DOTA-c(RGDfK) was labeled with 111In or 90Y and purified by HPLC. A biodistribution study and scintigraphic images revealed the specific uptake to alpha(v)beta(3) integrin and the rapid clearance from normal tissues. These peptides were renally excreted. At 10 min after injection of tracers, 111In-DOTA-c(RGDfK) and 90Y-DOTA-c(RGDfK) showed high uptake in tumors (7.3 +/- 0.6% ID/g and 4.6 +/- 0.8% ID/g, respectively) and gradually decreased over time (2.3 +/- 0.4% ID/g and 1.5 +/- 0.5% ID/g at 24 hr, respectively). High tumor-to-blood and -muscle ratios were obtained from these peptides. In radionuclide therapeutic study, multiple-dose administration of 90Y-DOTA-c(RGDfK) (3 x 11.1 MBq) suppressed tumor growth in comparison to the control group and a single-dose administration (11.1 MBq). Monomeric RGD peptides, 111In-DOTA-c(RGDfK) and (90)Y-DOTA-c(RGDfK), could be promising tracers for alpha(v)beta(3) integrin-targeting imaging and radiotherapy.

To review the outcome of successive surgery, chemotherapy and abdomino-pelvic radiotherapy in ovarian cancer; 212 patients who had been treated with surgery, chemotherapy, and APRT, during 10 years were studied. The patients ranged in age from 23 to 76 years (median 53). International Federation of Gynecology and Obstetrics staging showed 32 patients in stage Ic, 57 in stage II and 123 in stage III. Serous carcinoma was the most frequent type. Most of the patients had grade 1 histology. The majority had undergone optimal cytoreductive surgery. They were put on platinum-based chemotherapy and got APRT. Chemotherapy was started before, after or three courses before and three after radiation. Radiotherapy was delivered using Cobalt-60 anterior posterior fields to encompass the peritoneal cavity. They received at least 2000 cGy to abdomen and 5000 cGy to the pelvis. Minimum follow-up was 60 months. The result showed that most of the patients experienced RTOG grade 1 or 2 acute toxicities that responded to medication. Late complications were reasonable (3.8%), mostly were managed conservatively. Unplanned radiation interruptions were necessary in 42 patients (20%). Stage, grade and histology affected survival. Failure sites were abdomen in 35 cases, pelvis in 34, both pelvis and abdomen in 19 and distant metastasis in 34 cases. Overall, five-ear survival was 84.4%, 65%, 21% in stages Ic, II, III, respectively. We came to the conclusion that: Abdomino-pelvic radiotherapy is a safe adjuvant treatment in ovarian cancer and is well tolerated by most patients. Abdomino-pelvic radiotherapy does not significantly increase treatment complications in ovarian cancer. Radiation should be concerned in patients with high probability of recurrence of epithelial ovarian tumours.

Introduction: 2-Methoxyestradiol (2ME2) is an endogenous metabolite of the human hormone, estrogen, which has been shown to possess anti-tumor activity. 2-Fluoroethoxyestradiol (2FEE2) and 2-fluoropropanoxyestradiol (2FPE2), novel analogs of 2-methoxyestradiol, were designed and synthesized to be utilized as F-18 radiotracers for positron emission tomography (PET), with which the bio-distribution and intratumoral accumulations of 2ME2 could be measured in vivo for potential translation to human use., Methods: 2FEE2 and 2FPE2 were synthesized from 3,17beta-estradiol in five steps respectively. Drug-induced microtubule depolymerization, antiproliferative activity against human cancer cell lines and HIF-1alpha down-regulation by 2FEE2 and 2FPE2 were investigated to examine whether these molecules possess similar anti-tumor activities as 2-methoxyestradiol. 2-[(18)F]Fluoroethoxyestradiol was synthesized for PET., Results: Novel 2ME2 analogs, 2FEE2 and 2FPE2, were synthesized in 29% and 22% overall yield, respectively. 2FEE2 and 2FPE2 showed microtubule depolymerization and cytotoxicities against the human ovarian carcinoma cell line, 1A9, and the human glioma cell line, LN229. HIF-1alpha was down-regulated by 2FEE2 and 2FPE2 under hypoxic conditions. 2FEE2 was chosen as an F-18 radiotracer candidate, since it showed stronger antiproliferative activity than 2ME2 and 2FPE2. 2-[(18)F]Fluoroethoxyestradiol (2[(18)F]FEE2) was prepared in 8.3% decay-corrected yield in 90 min, based on a production of H[(18)F]F with more than 98% radiochemical purity., Conclusions: 2FEE2 and 2FPE2 showed similar activity as 2ME2. 2[(18)F]FEE2 was synthesized to be utilized as a PET radiotracer to measure the biological efficacy of 2ME2 and its analogs in vivo.

Struma ovarii is a rare monodermal ovarian teratoma composed predominantly of mature thyroid tissue. We describe herein the case of a 22-year-old woman who underwent a right salpingo-oophorectomy for struma ovarii at the age of 12 years, who was admitted 8 years later with signs and symptoms of a left pelvic tumor. Laparoscopy detected a left ovarian endometriotic cyst and multiple nodules on the pelvic peritoneum, right lateral abdominal wall, diaphragm, vesical plica and liver. The diagnosis was abdominal and pelvic widespread dissemination of recurrent struma ovarii, with features consistent with the follicular variant of papillary thyroid carcinoma. The patient was treated with a combination of conservative surgery and two 131I administrations (cumulative activity of 350 mCi after dosimetric evaluation). Because of the high degree of hormonogenesis shown by the metastases, the first administration was performed following use of recombinant human (rh) thyroid-stimulating hormone (TSH) to reach adequate TSH levels. To avoid the 'stunning effect' and to obtain high-quality scintigraphy, a whole-body scan was performed with 123I after rh-TSH and before the 131I therapy. We also discuss the potential role and the possible benefit of using gonadotropin-releasing hormone analogs and ovarian tissue cryopreservation to preserve fertility in women treated with 131I for pelvic metastases from malignant struma ovarii.

Escherichia coli nitroreductase (NTR) converts the prodrug CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) into a bifunctional alkylating agent that causes DNA crosslinks. In this study, the ability of NTR to enhance the combined effects of CB1954 and radiation has been tested in vitro and in vivo. Stably transduced ovarian cancer cells (SKOV3-NTR) that are sensitive to CB1954 (IC(50)=0.35 muM) demonstrated enhanced cytotoxicity when treated with CB1954 and single-fraction irradiation. The NTR-CB1954 system mediated a bystander effect in combination with radiation on transfer of conditioned medium from SKOV3-NTR, but not SKOV3, cells to SW480 target cells. The ability of CB1954 to enhance radiation-induced cytotoxicity in SKOV3-NTR (but not SKOV3) cells was also demonstrated by fluorescence-activated cell sorting (FACS) with dual staining for propidium iodide/fluorescein diacetate, 4',6-diamidino-2-phenylindole dichloride staining of apoptotic cells and measurement of double-stranded DNA breaks by FACS and confocal microscopy for gammaH2AX foci. Adenoviral delivery of NTR, under constitutive cytomegalovirus or tissue-specific CTP1 promoters, increased the in vitro cytotoxicity of CB1954 plus radiation in MTT and clonogenic assays. Finally, adenoviral delivery of NTR plus CB1954 enhanced the effect of fractionated radiotherapy (12 Gy in four fractions) in SW480 xenograft tumours in nude mice.

Purpose: To describe a new intensity-modulated radiotherapy (IMRT) technique using helical tomotherapy for whole abdominal irradiation (WAI) in patients with advanced ovarian cancer., Material and Methods: A patient with radically operated ovarian cancer FIGO stage IIIc was treated in a prospective clinical trial with WAI to a total dose of 30 Gy in 1.5-Gy fractions as an additional therapy after adjuvant platinum-based chemotherapy. The planning target volume (PTV) included the entire peritoneal cavity. PTV was adapted according to breathing motion as detected in a four-dimensional respiratory-triggered computed tomography (4D-CT). Inverse treatment planning was done with the Hi-Art tomotherapy planning station. Organs at risk (OARs) were kidneys, liver, bone marrow, spinal cord, thoracic and lumbosacral vertebral bodies, and pelvic bones. Daily control of positioning accuracy was performed with megavoltage computed tomography (MV-CT)., Results: Helical tomotherapy enabled a very homogeneous dose distribution with excellent sparing of OARs and coverage of the PTV (V90 of 93.1%, V95 of 86.9%, V105 of 1.9%, and V110 of 0.01%). Mean liver dose was 21.57 Gy and mean kidney doses were 9.75 Gy and 9.14 Gy, respectively. Treatment could be performed in 18.1 min daily and no severe side effects occurred., Conclusion: Helical tomotherapy is feasible and fast for WAI. Tomotherapy enabled excellent coverage of the PTV and effective sparing of liver, kidneys and bone marrow.

Purpose: To describe the clinical characteristics and estimate the survival of children and adolescents with germ cell tumors treated with cisplatin-based combination chemotherapy according to three different protocols in Brazil., Methods: From 1983 to 1997, 106 patients were treated at the Hospital do Cancer, Sao Paulo for a diagnosis of germ cell tumor. We performed a retrospective review of the clinical and histopathological data to identify prognostic factors and evaluate their outcome., Results: Patients were treated with only surgery (n = 32), surgery and radiotherapy (n = 1) and chemotherapy (n = 73). From 1983 to 1986 (period I), there were 30 patients and 21 received chemotherapy according to the modified VAB-6 protocol. Twenty-two of 35 patients registered between 1987 and 1991 (period II) were treated with EPO/VAC combination chemotherapy. From 1991 to 1997 (period III), there were 41 patients and 31 received chemotherapy according to the Brazilian TCG-91 protocol. Important prognostic factors included stage (P < 0.001), metastatic status (P < 0.001) and surgical procedure at diagnosis (P < 0.001). An incremental improvement in outcomes was noted across the periods of treatment (P = 0.070). Five-year OS was respectively 42.9 +/- 10.8%, 53.9 +/- 11.4% and 80.6 +/- 7.1% for periods I, II, and III for the patients who received chemotherapy., Conclusion: An improvement in the survival of children with germ cell tumors was achieved in the most recent trial (TCG-91) with a risk adapted approach incorporating only cisplatin and etoposide. These results indicate that in selected patients complex three-agent regimens may not be necessary to achieve long term survival., ((c) 2007 Wiley-Liss, Inc.)

Brain metastases from gynecological cancers were retrospectively investigated in 18 patients who were treated between 1985 and 2006. Six patients received surgical resection followed by radiotherapy, and 12 patients received only radiotherapy. The median survival for all patients was 4.1 months (range 0.7-48.2 months), and the actuarial survival rates were 11% at both 12 months and 24 months. Univariate analysis showed that treatment modality, extracranial disease status, total radiation dose, number of brain metastases, and Karnofsky performance status (KPS) all had statistically significant impacts on survival. Two patients survived for more than 2 years, and both had single brain metastasis, inactive extracranial disease, 90-100% KPS, and were treated with surgical resection followed by radiotherapy. Improvements in neurological symptoms were observed in 10 of the 12 patients treated with palliative radiotherapy, with median duration of 3.1 months (range 1.5-4.5 months). The prognoses for patients with brain metastases from gynecological cancers were generally poor, although selected patients may survive longer with intensive brain tumor treatment. Palliative radiotherapy was effective in improving the quality of the remaining life for patients with unfavorable prognoses.

This paper studies the apoptosis of human ovarian carcinoma cell Line (SKOV3) induced by the nanosecond pulsed electric field (10kV/cm, 100ns, 1 Hz) and its effect on intracellular calcium concentration ([Ca2+]i). These cells were doubly marked by Annexin V-FITC/PI, and the apoptosis rate was analyzed with flow cytometry. After AO/EB staining the morphological changes were observed under fluorescent microscope, and their ultrastructural changes were observed under scanning electron microscope (SEM). With Fluo-3/AM as calcium fluorescent marker, laser scanning confocal microscope (LSCM) was used to detect the effect of nsPEF on [Ca2+]i and the source of Ca2+. The results showed that the early apoptosis rate of the treatment group was (22.21+/-2.71)%, significantly higher than that of the control group (3.04+/-0.44)% (P<0.01). The typical features of apoptotic cell have been observed by fluorescent microscope and SEM. It is proved that nsPEF can induce apoptosis of SKOV3 cells and result in distinct increase in [Ca2+]i (P0.01), which was independent of extracellular calcium concentration (P>0.05). Since nsPEF can penetrate cell membrane due to its high frequency components, one of the mechanisms of nsPEF-induced apoptosis may be that activating intracellular calcium stores can increase the [Ca2+]i, and consequently, the apoptotic signal pathway can be induced.

Purpose: Among gynecologic malignancies, ovarian cancer has the highest mortality due to rapid peritoneal dissemination. Treatment failure particularly arises from failure to eliminate disseminated cells. Our aim was to develop peptidic radioligands targeting tumour cell-associated urokinase receptor (uPAR, CD87) for alpha-emitter therapy for advanced ovarian cancer., Methods: DOTA-conjugated, uPAR-directed ligands were synthesised on solid-phase. Binding of peptides to human cells expressing uPAR was assayed by flow cytofluorometry or, in case of (213)Bi-labelled peptides, by measuring cell-bound radioactivity. Bio-distribution of the (213)Bi-labelled peptide P-P4D was analysed in nude mice 28 days after intraperitoneal inoculation of OV-MZ-6 ovarian cancer cells in the absence or presence of the plasma expander gelofusine., Results: uPAR-selective ligands were developed based on published high-affinity uPAR-binding peptides. For preparation of N-terminally cross-linked divalent ligands, a novel solid-phase procedure was developed. Specific binding of (213)Bi-labelled peptides to monocytoid U937 and OV-MZ-6 cells was demonstrated using the natural ligand of uPAR, pro-uPA, or a soluble form of uPAR, suPAR, as competitors. The pseudo-symmetrical covalent dimer (213)Bi-P-P4D displayed superior binding to OV-MZ-6 cells in vitro. Accumulation of (213)Bi-P-P4D in tumour tissue was demonstrated by bio-distribution analysis in nude mice bearing intraperitoneal OV-MZ-6-derived tumours. Gelofusine reduced kidney uptake of (213)Bi-P-P4D by half., Conclusion: Ovarian cancer cells overexpressing uPAR were specifically targeted in vitro and in vivo by (213)Bi-P-P4D. Kidney uptake of (213)Bi-P-P4D was distinctly reduced using gelofusine. Thus, this radiopeptide may represent a promising option for therapy for disseminated ovarian cancer.

Purpose: Control of ovarian cancer (OC) ascites remains a major objective in post-surgical treatment. The aim of this study was to investigate the effect of targeted alpha therapy (TAT) for the control of ascites in an OC ascites mouse model; the biodistribution of (213)Bi-C595 and its long term toxicity., Methods: The expression of tumor-associated antigen mucin-1 (MUC-1) in OVCAR3 ascites cells in mice and OC cancer tissues in patients was detected by indirect immmunostaining. The monoclonal antibody (MAb) C595 was labeled with (213)Bi using the chelator cDTPA to form the alpha-immunoconjugate (AIC). Mice were injected with different concentrations of AIC by i.p administration. Changes in tumor progression were assessed by measurement of the circumference of the abdomen., Results: MUC-1 is strongly expressed in 73% of OC tissues. At 9 days post-cell inoculation in mice, a single injection of 355 MBq/kg of (213)Bi-C595 can prolong survival by 25 days. A high tumor: blood ratio (5.8) was found in biodistribution study. The maximum tolerance dose (MTD) was more than 1180 MBq/kg up to 21 weeks., Conclusions: C595 is a specific targeting vector for ovarian cancer cells, which show a high percentage of expression of MUC1. (213)Bi-C595 can effectively target and kill ovarian cancer cells in vitro and in vivo. (213)Bi-C595 is the recommended alpha conjugate for a Phase I clinical trial for ovarian cancer.

Background: The prognosis for patients with advanced epithelial ovarian cancer remains poor despite aggressive surgical resection and platinum-based chemotherapy. More than 60% of patients will develop recurrent disease, principally intraperitoneal, and die within 5 years. The use of whole abdominal irradiation (WAI) as consolidation therapy would appear to be a logical strategy given its ability to sterilize small tumour volumes. Despite the clinically proven efficacy of whole abdominal irradiation, the use of radiotherapy in ovarian cancer has profoundly decreased mainly due to high treatment-related toxicity. Modern intensity-modulated radiation therapy (IMRT) could allow to spare kidneys, liver, and bone marrow while still adequately covering the peritoneal cavity with a homogenous dose., Methods/design: The OVAR-IMRT-01 study is a single center pilot trial of a phase I/II study. Patients with advanced ovarian cancer stage FIGO III (R1 or R2< 1 cm) after surgical resection and platinum-based chemotherapy will be treated with whole abdomen irradiation as consolidation therapy using intensity modulated radiation therapy (IMRT) to a total dose of 30 Gy in 1.5 Gy fractions. A total of 8 patients will be included in this trial. For treatment planning bone marrow, kidneys, liver, spinal cord, vertebral bodies and pelvic bones are defined as organs at risk. The planning target volume includes the entire peritoneal cavity plus pelvic and para-aortic node regions., Discussion: The primary endpoint of the study is the evaluation of the feasibility of intensity-modulated WAI and the evaluation of the study protocol. Secondary endpoint is evaluation of the toxicity of intensity modulated WAI before continuing with the phase I/II study. The aim is to explore the potential of IMRT as a new method for WAI to decrease the dose to kidneys, liver, bone marrow while covering the peritoneal cavity with a homogenous dose, and to implement whole abdominal intensity-modulated radiotherapy into the adjuvant multimodal treatment concept of advanced ovarian cancer FIGO stage III.

Aim: Radionuclide imaging of the HER2 receptor, which is a target for trastuzumab therapy, can provide important diagnostic information. Further, targeting radionuclide therapy might be an option for treatment of HER2 expressing tumors. The phage-display selected Affibody ligand Z(HER2:342), which binds to HER2 with an affinity of 22 pM, may here play an important role. The small size of the Z(HER2:342), 7.5 kDa, enables quick tumor localization and fast blood clearance. Earlier, successful targeting of HER2-expressing xenografts using Z(HER2:342) labeled using [(111)In]benzyl-DTPA was reported. By changing to the CHX-A''-DTPA chelator, the stability and labeling kinetics of the radiometal-Z(HER2:342) conjugate can be improved. The aim of this study was to evaluate the labeling of the CHX-A''-DTPA-Z(HER2:342) conjugate with (111)In for diagnostic imaging and with (114m)In for locoregional radionuclide therapy., Methods: The isothiocyanate derivative of CHX-A''-DTPA was coupled to Z(HER2:342) in alkaline conditions at 37 degrees C. The conjugate was labeled with both (111)In and (114m)In and evaluated in vitro and in vivo., Results: Labeling with (111)In and (114m)In provided >95% yield after 30 min at RT. Specific radioactivity was 0.5 and 12 MBq/nmol, for (114m)In and (111)In, respectively. The radiolabeled conjugates demonstrated specific binding to HER2 expressing SKOV-3 cells. In mice bearing SKOV-3 xenografts, the tumor uptake of [(111)In]CHX-A''-DTPA-Z(HER2:342) 4 h postinjection was 10.3+/-3.6% IA/g and tumor-to-blood ratio about 190., Conclusion: [(111)In]CHX-A''-DTPA-Z(HER2:342) is a promising candidate for the visualization of HER2 expression in malignant tumors. Labeled with (114m)In it could also be used for locoregional treatment of HER2 expressing tumors.

Objectives: The aim of this study was to clarify the efficacy of postoperative whole abdominal radiotherapy (WAR) for ovarian clear cell adenocarcinoma (OCCA)., Methods: Between 1996 and 2004, 16 patients with OCCA underwent initial debulking surgery and received postoperative WAR. Indications for WAR were as follows: OCCA, International Federation of Gynaecology and Obstetrics (FIGO) stage Ic-III, no macroscopic residual disease in the upper abdomen and residual disease in the pelvic cavity < or = 2 cm. The planned WAR comprised external beam radiotherapy (EBRT) to the entire abdominal cavity with 22.0-24.0 Gy/22-24 fractions followed by EBRT to the pelvis with 23.4-21.6 Gy/12-13 fractions. Overall survival (OS) and disease-free survival (DFS) were compared with 12 historical control (HC) patients treated with initial debulking surgery followed by platinum-based chemotherapy., Results: The FIGO stage in the WAR group was stage Ic in 11 patients, stage II in 3, and stage III in 2. Fifteen of the 16 patients (94%) completed the planned WAR. Two patients developed radiation enterocolitis and required bowel surgery. Five-year OS and DFS in the WAR/HC group were 81.8%/33.3% and 81.2%/25.0% (p=0.031 and p=0.006), respectively., Conclusions: This study suggests that postoperative WAR may be effective in selected patients with OCCA. Prospective randomized trials should be considered to assess postoperative WAR for OCCA.

In recent years, a number of new developments in targeted therapies using radiolabeled compounds have emerged. New developments and insights in radioiodine treatment of thyroid cancer, treatment of lymphoma and solid tumors with radiolabeled monoclonal antibodies (mAbs), the developments in the application of radiolabeled small receptor-specific molecules such as meta-iodobenzylguanidine and peptides and the position of locoregional treatment in malignant involvement of the liver are reviewed. The introduction of recombinant human thyroid-stimulating hormone and the possibility to enhance iodine uptake with retinoids has changed the radioiodine treatment protocol of patients with thyroid cancer. Introduction of radiolabeled mAbs has provided additional treatment options in patients with malignant lymphoma, while a similar approach proves to be cumbersome in patients with solid tumors. With radiolabeled small molecules that target specific receptors on tumor cells, high radiation doses can be directed to tumors in patients with disseminated disease. Radiolabeled somatostatin derivatives for the treatment of neuroendocrine tumors are the role model for this approach. Locoregional treatment with radiopharmaceuticals of patients with hepatocellular carcinoma or metastases to the liver may be used in inoperable cases, but may also be of benefit in a neo-adjuvant or adjuvant setting. Significant developments in the application of targeted radionuclide therapy have taken place. New treatment modalities have been introduced in the clinic. The concept of combining therapeutic radiopharmaceuticals with other treatment modalities is more extensively explored.

Purpose: To investigate the potential use of astatine-211 (211At)-labeled trastuzumab for the treatment of HER-2-positive, radioresistant ovarian carcinoma., Methods and Materials: Four-week-old nude mice were inoculated intraperitoneally with 5 . 10(6) SKOV-3 cells in 0.4 mL saline on Day 0. The endpoint was the total tumor weight in each mouse on Day 63. Three experiments were performed in which the response to single-dose and fractionated treatment with unlabeled and 211At-labeled antibody was evaluated., Results: Experiment 1 showed, for the same total amount of trastuzumab, a dose-response relationship between 211At activity (0-400 kBq on Day 7) and therapeutic efficacy (p = 0.001). The effect of varying the amount of unlabeled trastuzumab was studied in Experiment 2. All mice, except for the controls, received 400 kBq 211At-trastuzumab, and different groups received 5, 50, or 500 microg trastuzumab on Day 7. The increase from 5 to 50 microg trastuzumab reduced the tumors by 78% in weight. No tumors were present in mice given 500 microg trastuzumab. In Experiment 3, the effect of a fractionated treatment regimen was studied. Mice that received 100 kBq 211At-trastuzumab on Days 7 and 8 had a 42% smaller tumor burden than did controls. Groups of mice injected with 200 + 100 kBq on Days 7 and 21 and mice injected with 100 kBq on Days 7, 8, and 21 both had 24% less tumor weight than the corresponding controls., Conclusion: The combination of 500 microg trastuzumab and 400 kBq 211At-trastuzumab had the greatest effect, with complete eradication of the tumors in this nude mouse model.

Purpose: This study was designed to retrospectively evaluate the diagnostic yield of FDG PET for the diagnosis of recurrent ovarian cancer., Methods: Eighty FDG PET scans were performed on 55 patients owing to suspicion of relapse, and 45 FDG PET scans were performed on 31 patients who were clinically disease free. PET results were compared with the results of conventional radiological imaging (CIM) and serum CA 125 levels, and related to pathological findings in 54 cases or clinical follow-up in 71 cases., Results: CIM correctly identified 49 cases with recurrence [sensitivity (SE) 53.3%] ,and there were 27 true negatives [specificity (SP) 81.8%] However, 43 cases were false negative and six were false positive. The positive predictive value (PPV), negative predictive value (NPV) and accuracy (ACC) of CIM were 89%, 38.6% and 60.8%, respectively. FDG PET correctly detected recurrent disease in 80/92 cases (SE 86.9%, p<0.05) and ruled out relapse in 26/33 cases (SP=78.8%). The PPV, NPV and ACC of PET were 91.9%, 68.4% and 84.8%, respectively. Standardised uptake values did not provide additional diagnostic accuracy compared with visual analysis. The CA 125 results showed an SE of 57.6%, an SP of 93.9% and an ACC of 67.2%. In 23 patients with positive serum CA 125 levels, but negative CIM, FDG PET was positive and relapse was confirmed. Furthermore, FDG PET was positive and relapse was confirmed in 11 patients with negative serum CA 125 levels and CIM., Conclusion: FDG PET may detect recurrent ovarian cancer earlier than CIM, with higher sensitivity and even higher diagnostic accuracy.

We conducted a single-arm study to determine the biodistribution of intraperitoneally (i.p.) administered 90yttrium-labeled murine monoclonal antibody HMFG1 (90Y-muHMFG1) in patients with advanced stage ovarian cancer. Seventeen (17) patients in complete clinical remission for epithelial ovarian cancer were included. After completion of chemotherapy, a mixture of 111indium-labeled muHMFG1 (imaging) and 90Y-muHMFG1 (therapy) was i.p. administered by a surgically placed, indwelling i.p. catheter. Planar and single-photon emission computed tomography images were recorded to determine the distribution of the study medication during the first 6 days postinjection. Of the first 3 patients, 2 patients had extraperitoneal leakage of up to 50% of the injected dose within 24 hours after injection of the study medication. Extraperitoneal leakage was mainly seen in the retroperitoneal spaces covering the upper and lower quadrant of the abdomen. After adjustments in the procedure, leakage was observed in 2 of the remaining 14 patients. Extraperitoneal leakage of i.p. administered therapy does occur. Such leakage would reduce the locally delivered dose of a drug and could potentially have a negative impact on therapeutic efficacy. Given the potential attraction of developing i.p. treatments for intra-abdominal cancer, the observations in this study need to be taken into consideration.

Single antigen-targeted intraperitoneal radioimmunotherapy for ovarian cancer has shown limited success. Due to the heterogeneous expression of tumor antigens on cancer cells, a multi-antigen targeting approach appears logical to augment the therapeutic efficacy of antibody-guided therapy. In the interest of developing this novel approach, ovarian cancer tissue microarray slides containing cancer and benign/non-neoplastic tissue samples (n=92) were processed for single-, double-, and triple-antigen labeling using antibodies for the tumor-associated antigens TAG-72, MUC1, and CA125. Among all ovarian cancer types, 72%, 61%, and 50% of the samples showed immunolabeling for TAG-72, MUC1, and CA125, respectively. Expression level of these antigens was significantly (p<0.005) higher in advanced stage carcinomas compared with early stage. Of the 48 epithelial ovarian cancer samples, individual anti-TAG-72, MUC1, and CA125 antibody probing showed labeling in 89.5%, 87.5%, and 73.0% of the cases, respectively. In the majority of the cancer samples (>70%), a heterogeneous labeling pattern was observed (only 30-40% of the cancer cells within the sample were labeled). However, upon combining the three antigens (triple-antigen labeling), 98% of the epithelial ovarian cancer samples were labeled and >95% of the cancer cells within each sample were labeled. Our data indicate that the heterogeneous expression of cancer antigens appears to be a major obstacle in antibody-guided therapy, and this can be overcome by multiple antigen targeting. Therapeutic efficacy of antibody-guided therapy for ovarian cancer treatment will be enhanced by the combined targeting of TAG-72, MUC1, and CA125.

Purpose: Necrosis is the most common morphologic alteration found in tumors and surrounding normal tissues after radiation therapy or chemotherapy. Accurate measurement of necrosis may provide an early indication of treatment efficacy or associated toxicity. The purpose of this report is to evaluate the selective accumulation of polymeric paramagnetic magnetic resonance (MR) contrast agents--gadolinium p-aminobenzyl-diethylenetriaminepentaacetic acid-poly(glutamic acid) (L-PG-DTPA-Gd and D-PG-DTPA-Gd)--in necrotic tissue., Methods and Materials: Two different solid tumor models, human Colo-205 xenograft and syngeneic murine OCA-1 ovarian tumors, were used in this study. Necrotic response was induced by treatment with poly(L-glutamic acid)-paclitaxel conjugate (PG-TXL). T(1)-weighted spin-echo images were obtained immediately and up to 4 days after contrast injection and compared with corresponding histologic specimens. Two low-molecular-weight contrast agents, DTPA-Gd and oligomeric(L-glutamic acid)-DTPA-Gd, were used as nonspecific controls., Results: Initially, there was minimal tumor enhancement after injection of either L-PG-DTPA-Gd or D-PG-DTPA-Gd, but rapid enhancement after injection of low-molecular-weight agents. However, polymeric contrast agents, but not low-molecular-weight contrast agents, caused sustained enhancement in regions of tumor necrosis in both tumors treated with PG-TXL and untreated tumors. These data indicate that high molecular weight, rather than in vivo biodegradation, is necessary for the specific localization of polymeric MR contrast agents to necrotic tissue. Moreover, biotinylated L-PG-DTPA-Gd colocalized with macrophages in the tumor necrotic areas, suggesting that selective accumulation of L- and D-PG-DTPA-Gd in necrotic tissue was mediated through residing macrophages., Conclusions: Our data suggest that MR imaging with PG-DTPA-Gd may be a useful technique for noninvasive characterization of treatment-induced necrosis.

Background: Serous ovarian tumors of low malignant potential (STLMP) frequently coexist with low-grade serous carcinoma of the ovary (LGSC) and, when they recur, frequently do so as LGSC. The purpose of this study was to compare the outcomes of patients with these two tumor types., Methods: All patients with stages II-IV LGSC (group 1) or with STLMP that recurred as LGSC (group 2) seen at our institution from 1973 to 2003 were identified, and demographic data were obtained. For group 1, progression-free and overall survival times were calculated from the date of primary diagnosis to the date of disease progression/recurrence or the date of last contact/death, respectively. For group 2, progression-free and overall survival times were calculated from the date of first relapse as a LGSC to the date of progression or the date of last contact/death, respectively. The method of Kaplan and Meier was used to estimate survival, and the log-rank test was used to compare differences between survival curves., Results: We identified 112 patients in group 1 and 41 in group 2. There were no statistically significant differences between the two groups in median age (42.7 vs. 45.4 years [at relapse]; P=0.37), progression-free survival time (19.5 vs. 25 months; P=0.92), or overall survival time (81.8 vs. 82.8 months; P=0.84)., Conclusions: The age at diagnosis, progression-free survival time, and overall survival time associated with newly diagnosed stages II-IV LGSC of the ovary are similar to those of STLMP that recur as LGSC, providing further evidence of an association between these two tumor types.

Purpose: There are few studies of somatic and mental morbidity in epithelial ovarian cancer survivors (EOCSs). The aim of this controlled, cross-sectional study was to explore fatigue, quality of life (QOL), and somatic and mental morbidity in EOCSs., Patients and Methods: Among 287 EOCSs treated according to protocols at The Norwegian Radium Hospital between 1977 and 2003, 189 patients (66%) participated. Information was collected by a questionnaire containing demographic and morbidity items and self-rating scales. Internal comparisons of various subgroups of EOCSs were performed, and EOCSs were compared with age-adjusted controls from the general population., Results: Minimal differences were observed relating to somatic and mental morbidity, fatigue, and QOL between EOCSs with and without relapse, long or short follow-up time, and prognostic index status. Chronic fatigue was found in 22% (95% CI, 16% to 28%), and only body image was significantly associated with chronic fatigue in multivariable analyses. EOCSs showed significantly more somatic and mental morbidity, somatic complaints, use of medications, and use of health care services than controls. The levels of anxiety and fatigue were also significantly higher in EOCSs than in controls, whereas the levels of depression and of several QOL dimensions were lower. The prevalence of chronic fatigue was 12% among controls., Conclusion: EOCSs had more somatic and mental morbidity, more fatigue, poorer QOL, and used more medication and health services than controls. Minimal differences were observed between various EOCS subgroups. Health care professionals should try to improve and be attentive to the health of EOCSs.

Background: Aggressive chemotherapy/radiotherapy for cancer may cause gonadal failure in young female survivors. The putative aim of ovarian tissue cryopreservation is to restore fertility by transplantation of a patient's frozen-thawed ovarian tissue or, further into the future, by in vitro maturation of frozen-thawed oocytes followed by in vitro fertilization. This report presents our early experience with ovarian tissue preservation in young patients., Methods: We conducted a database review of the techniques and outcomes of the ethics board-approved ovarian tissue cryopreservation procedures performed at our center since 1998 for young girls with malignancy., Results: The study group included 23 patients (median age = 14 years) with various types of cancer (hematologic, bone, ovarian, or intracranial); 11 patients were scheduled for chemotherapy, 11 patients had already undergone some form of chemotherapy before the ovarian tissue harvesting, and 1 patient was not scheduled for chemotherapy. Ten underwent bone marrow transplantation after tissue retrieval. Twenty-one patients underwent laparoscopic harvesting of their ovarian tissue. In the other 2 patients, the ovary was preserved during inguinal hernia repair or tissue was obtained at laparotomy for a pelvic tumor. All patients had benign operative and postoperative courses., Conclusions: Laparoscopy for ovarian tissue retrieval for cryopreservation is safe in young cancer patients. Based on reports of successful cryopreservation of human ovarian tissue containing primordial follicles, we believe that this approach holds promise for female cancer survivors.

Epithelial ovarian cancer is the gynecological tumor with the highest mortality rate. Recently, numerous findings have emerged on the status and extent of surgical therapy for this disease. Innovations in the chemotherapy of primary and recurrent disease are also plentiful. It is essential for the improvement of the patients' situation to transfer these new developments, already integrated into national and international standards and guidelines, into clinical practice.

Background: Unfertilized oocytes, embryos and ovarian issue can be cryopreserved before cancer treatment of post-pubertal women. Fertility may be restored by retransplantation in women who are pronounced healthy., Material and Methods: The article is based on relevant literature and our own clinical experience since 2004, when the procedure was first allowed in Norway., Results and Interpretation: Cryopreservation of ovarian tissue is an established procedure in Norway. As of January 2007, ovarian tissue from 22 women, aged 14-35 years, has been cryopreserved at Rikshospitalet. There is an upper age limit of 35 years because of age-related follicular loss. The treating oncologist and a gynaecologist should be responsible for informing patients about the possibility of preserving fertility by ovarian cryopreservation before chemo- and/or radiation therapy. The patient should, at the same time, be told about the limited world-wide experience with this procedure.

Multiple carcinomas of the genital system are rare in the literature. We report a 43-year-old female patient who presented with 3 different synchronous primary genital system malignancies (cervix, endometrium and ovary). After Wertheim's hysterectomy there was a 4 x 2 cm residual mass for which systemic chemotherapy and radiotherapy were administered. The patient rapidly deteriorated and died due to disease progression. Registration of cases with multiple tumors in a single centre using a standardized investigation for predisposing parameters may contribute much to the management of such conditions.

Objectives: To assess compliance to current surgical staging and adjuvant treatment guidelines for patients with early-stage epithelial ovarian carcinoma and its impact on overall survival., Methods: Patients diagnosed between 1991 and 1997 with early-stage ovarian cancer were recruited from the Regional Cancer Registry of the central region in the Netherlands. Demographic data, tumour characteristics, surgical findings and therapeutic data were abstracted from medical records. Patients were classified into optimal and non-optimal surgical staging. Overall survival was estimated using Kaplan-Meier method. To adjust for age hazard ratios for overall survival were estimated with a Cox Proportional Hazards model., Results: One hundred and twenty-five patients were included in the study, 41 of them (32.8%) were optimally staged. Guidelines for adjuvant radio- or chemotherapy were adequately followed in all 62 grade I patients and in 44 out of 59 grade II and III patients (74.6%). During 734.6 person-years of follow up 31 patients died. Five-year overall survival figures were 97.6% in the optimally staged group and 68.5% in the non-optimally staged group. Patients who were non-optimally staged, had a significant higher risk to die than those who were optimally staged (HR: 7.4; 95% CI: 1.7-32.2). In patients with a grade II and III tumours, complete surgical staging still had a significant influence on survival (HR: 3.8; 95% CI 1.7-8.3). In women with grade II or III tumours, adjuvant radio- or chemotherapy administered in accordance to the guidelines did not improve overall survival regardless whether they were optimally staged or not., Conclusion: Incomplete staging in early-stage ovarian cancer leads to gross mis-classification in grade II and III tumours and to a lesser extent in grade I tumours. This leads to undertreatment in both surgical and adjuvant therapy. Subsequently unnecessary deaths may occur. More effort must be put in identifying obstacles interfering with compliance of guidelines.

Purpose: 130-nm albumin-bound paclitaxel (nab-paclitaxel) is a novel solvent-free albumin-bound paclitaxel, designed to avoid solvent-related toxicity. Nab-paclitaxel has been successfully introduced into the clinic but its radiation-enhancing potential has not yet been evaluated. We conducted a preclinical evaluation of the radiation-modulating effects of nab-paclitaxel in tumor and normal tissues., Experimental Design: Mice bearing syngeneic ovarian or mammary carcinomas were treated with nab-paclitaxel, radiation, or combination of both. Nab-paclitaxel was administered at 90 mg/kg, 1.5 times the maximum tolerated dose for solvent-based paclitaxel. End points were antitumor efficacy (growth delay, radiocurability, and cellular effects) and normal tissue toxicity (gut and skin)., Results: Nab-paclitaxel showed single-agent antitumor efficacy against both tumor types and acted as a radiosensitizer. Combined with radiation, nab-paclitaxel produced supra-additive effects when given before radiation. Nab-paclitaxel significantly increased radiocurability by reducing the dose yielding 50% tumor cure (TCD(50)) from 54.3 to 35.2 Gy. Tumor histology following nab-paclitaxel treatment was characterized by pronounced necrotic and apoptotic cell death and mitotic arrest. Nab-paclitaxel did not increase normal tissue radioresponse., Conclusions: Nab-paclitaxel exhibited strong antitumor efficacy against both tumors as a single agent and it improved radiotherapy in a supra-additive manner. These improved effects were achieved without increased normal tissue toxicity to either rapidly or slowly proliferating normal tissues although the drug dose was 1.5 times higher than the maximum tolerated dose of solvent-based paclitaxel. These preclinical findings show that combining nab-paclitaxel with radiotherapy would improve the outcome of taxane-based chemoradiotherapy. This novel taxane is thus a good candidate for testing in clinical chemoradiotherapy trials.

A radiolabeled anti-HER2 Affibody molecule (Z(HER2:342)) targets HER2-expressing xenografts with high selectivity and gives good imaging contrast. However, the small size (approximately 7 kDa) results in rapid glomerular filtration and high renal accumulation of radiometals, thus excluding targeted therapy. Here, we report that reversible binding to albumin efficiently reduces the renal excretion and uptake, enabling radiometal-based nuclide therapy. The dimeric Affibody molecule (Z(HER2:342))(2) was fused with an albumin-binding domain (ABD) conjugated with the isothiocyanate derivative of CHX-A''-DTPA and labeled with the low-energy beta-emitter (177)Lu. The obtained conjugate [CHX-A''-DTPA-ABD-(Z(HER2:342))(2)] had a dissociation constant of 18 pmol/L to HER2 and 8.2 and 31 nmol/L for human and murine albumin, respectively. The radiolabeled conjugate displayed specific binding to HER2-expressing cells and good cellular retention in vitro. In vivo, fusion with ABD enabled a 25-fold reduction of renal uptake in comparison with the nonfused dimer molecule (Z(HER2:342))(2). Furthermore, the biodistribution showed high and specific uptake of the conjugate in HER2-expressing tumors. Treatment of SKOV-3 microxenografts (high HER2 expression) with 17 or 22 MBq (177)Lu-CHX-A''-DTPA-ABD-(Z(HER2:342))(2) completely prevented formation of tumors, in contrast to mice given PBS or 22 MBq of a radiolabeled non-HER2-binding Affibody molecule. In LS174T xenografts (low HER2 expression), this treatment resulted in a small but significant increase of the survival time. Thus, fusion with ABD improved the in vivo biodistribution, and the results highlight (177)Lu-CHX-A''-DTPA-ABD-(Z(HER2:342))(2) as a candidate for treatment of disseminated tumors with a high level of HER2 expression.

Ovarian cancer is the fourth most common cause of cancer deaths among females in the western world after cancer of the breast, colon and lung. The inability to control the disease within the peritoneal cavity is the major cause of treatment failure in patients with ovarian cancer. The majority of ovarian carcinomas express the alpha(v)beta(3) integrin. Here we studied the tumor targeting potential of an (111)In-labeled cyclic RGD peptide in athymic BALB/c mice with intraperitoneally (i.p.) growing NIH:OVCAR-3 human ovarian carcinoma tumors. The cyclic RGD peptide, c(RGDfK)E, was synthesized, conjugated with DOTA and radiolabeled with (111)In. The targeting potential of (111)In-DOTA-E-c(RGDfK) was studied in athymic mice with i.p. growing NIH:OVCAR-3 xenografts and the optimal dose of this compound was determined (0.01 microg up to 10 microg). The biodistribution at optimal peptide dose was determined at various time points (0.5 up to 72 hr). Furthermore, the therapeutic potential of (177)Lu-DOTA-E-c(RGDfK) was studied in this model. Two hours after i.p. administration, (111)In-DOTA-E-c(RGDfK) showed high and specific uptake in the i.p. growing tumors. Optimal uptake in the i.p. growing tumors was observed at a 0.03-0.1 microg dose range. Tumor uptake of (111)In-DOTA-E-c(RGDfK) peaked 4 hr p.i. [(38.8 +/- 2.7)% ID/g], gradually decreasing at later time points [(24.0 +/- 4.1)% ID/g at 48 hr p.i.]. Intraperitoneal growth of OVCAR-3 could be significantly delayed by injecting 37 MBq (177)Lu-labeled peptide i.p. Radiolabeled DOTA-E-c(RGDfK) is suitable for targeting of i.p. growing tumors and potentially can be used for peptide receptor radionuclide therapy of these tumors.

Underweight as a consequence of chronic diarrhoea may lead to fatigue, tiredness and impaired physical performance, especially when the underlying cause has not been evaluated. In spite of algorithms as a help in the differential diagnosis, an individual approach with critical consideration of diet history, laboratory data and imaging procedures is necessary. Additional difficulties may arise when the history of food intolerance is inconsistent and technical findings including endoscopy are inconclusive. We report on a 57-year-old female patient with underweight, chronic intermittent diarrhoea and cramp-like abdominal pain for more than 10 years following pelvic irradiation due to Hodgkin's disease of the ovary. A systematic diagnostic approach was not undertaken until very recently due to the deterioration of her clinical conditions pointing to jejunal malabsorption. In spite of the absence of a specific history of milk/milk product intolerance a lactose H (2)-breath test was performed showing lactase deficiency with lactose intolerance. The rapid improvement of all her symptoms after a lactose-poor diet had been started supported this diagnosis. Possible reasons for the long time period which had elapsed until the diagnosis was established and the discrepancy of the H (2)-breath test results with the absence of a clear-cut history for milk/milk product intolerance are discussed in terms of the importance of a structured history-taking with regard to nutrition and diet habits. In addition, potential explanations for radiation-induced functional damage in the absence of morphological abnormalities are provided. Based on the experience of this case and considerations regarding the consequences of radiation-induced jejunal damage, we recommend that a lactose-H (2) breath test be routinely included in the diagnostic work-up of patients with unclear chronic diarrhoea even if there is no defined history of milk/milk product intolerance.

Pertuzumab (Omnitarg) is a novel antibody against HER-2, domain II. HER-2 is a tyrosine kinase receptor that is overexpressed in several carcinomas, especially breast cancer. Pertuzumab, labeled with the low-energy beta emitter (177)Lu, might be a candidate for targeted radiotherapy of disseminated HER-2-positive micrometastases. The radiolabeled antibody [(177)Lu]pertuzumab showed favorable targeting properties in BALB/c (nu/nu) mice with HER-2-overexpressing xenografts. The absorbed dose in tumors was more than five times higher than the absorbed dose in blood and more than seven times the absorbed dose in any other normal organ. Experimental therapy showed that [(177)Lu]pertuzumab delayed tumor progression compared with controls (no treatment, P < 0.0001; nonlabeled pertuzumab antibody, P < 0.0001; and (177)Lu-labeled irrelevant antibody, P < 0.01). No adverse side effects of the treatment could be detected. Thus, the experimental results support the planning of clinical studies applying [(177)Lu]pertuzumab for therapy.

Ovarian cancer patients developing metastatic spinal cord compression (MSCC) are extremely rare and account for only 0.4% of MSCC patients. Only very few case reports are available in the literature. This analysis evaluates seven ovarian cancer patients treated for MSCC with radiotherapy alone. Data of 1,852 MSCC patients irradiated between 1992 and 2005 were retrospectively reviewed. Seven patients were identified with epithelial ovarian cancer. These seven patients were evaluated for functional outcome, ambulatory status, local control of MSCC, and survival. The patients received either short-course radiotherapy (1 x 8 Gy or 5 x 4 Gy, n= 2) or long-course radiotherapy (10 x 3 Gy, 15 x 2.5 Gy, or 20 x 2 Gy, n= 5). Improvement of motor function occurred in three of the seven patients, in three of the five patients after long-course radiotherapy, and none of the two patients after short-course radiotherapy. Two of the five nonambulatory patients regained the ability to walk after radiotherapy. No further deterioration of motor function was seen in another three of the seven patients, in two of the five patients after long-course radiotherapy, and one of the two patients after short-course radiotherapy. Deterioration occurred in one of the seven patients, in none of the five patients after long-course radiotherapy, and one of the two patients after short-course radiotherapy. Patients died after a median interval of 4 months (range 1-7 months) following radiotherapy. A recurrence of MSCC did not occur. Radiotherapy alone is effective in improving or maintaining motor function in MSCC patients with ovarian cancer and should be administered if decompressive surgery is not indicated.

Objective: This retrospective trial aims to report the treatment results of patients with locally advanced cervical cancer treated by concomitant radiochemotherapy with weekly cisplatin., Methods: Between October 1999 and December 2003, 81 patients with FIGO Stages IB-IVA were treated at Ege University Faculty of Medicine Department of Radiation Oncology by radiochemotherapy with weekly cisplatin (40 mg/m2). Intracavitary high-dose rate brachytherapy was applied to 76 patients (93.8%) and five patients (6.2%) were treated with external radiotherapy alone. Early and late side-effects of the treatment were analyzed according to RTOG-EORTC criteria., Results: Median age was 55 years and the most frequent histology was epidermoid carcinoma. Median follow-up time was 42 months. Five-year overall, disease-free and local relapse-free survival rates were 69%, 77%, and 82%, respectively. The presence of low Hgb level (< 12 g/dl), bulky tumor (> 4 cm), poor performance status, pelvic nodal involvement and limited early response to treatment had a significant impact on the local failure rate. Prognostic factors influencing disease-free survival were bulky tumor, performance status, pelvic nodal status, pretreatment Hgb level and limited early response to treatment. A significantly higher 5-year overall survival rate was observed in patients with good performance status, without pelvic nodal involvement, normal pretreatment Hgb level and complete response to treatment. Grade 3-4 side-effects were not observed in any patients. The most frequent acute side-effects were leukopenia, anemia, nausea and vomiting. Long-term side-effects were observed in 54% of patients., Conclusion: This series suggests that radiochemotherapy with weekly cisplatin is an effective and a safe treatment in locally advanced cervical cancer.

Background: The prognostic significance of age in ovarian cancer has not been clarified. We investigated the characteristics of ovarian cancer presenting in ages > 70 years and assessed the prognostic significance of advanced age., Patients and Methods: Four hundred and fifty-three patients with stage IIC-IV ovarian cancer (age>70 years n=106 [23%]), treated postoperatively with platinum-based chemotherapy were retrospectively reviewed., Results: Median overall survival (OS) of patients 570 years old (52.3 months, 95% CI: 43.2-61.3) was longer than that of older patients (38.8 months, 95% CI: 29.9-47.7) (p =0.005), but this difference was not significant in a multivariate analysis (p=0.978). Age >70 years was correlated with worse performance status (PS) (p=0.019), higher tumor grade (p=0.033), residual disease >2 cm (p=0.006) and less frequent paclitaxel administration (p<0.001). Toxicity from chemotherapy was similar between the two age groups, but the relative dose intensity of paclitaxel was lower among elderly patients., Conclusion: The worse outcome of ovarian cancer in elderly patients may be attributed to other associated adverse prognostic factors, but advanced age was not an independent prognostic factor.